Diagnosis: Warburg Micro syndrome

Warburg Micro syndrome (WMS), also called Micro syndrome, is a rare genetic disorder with autosomal recessive inheritance. It primarily affects vision, growth, and brain development, leading to delayed neurological development. Affected children exhibit severe intellectual disability and delayed or arrested psychomotor development at various developmental milestones.

Other characteristic features include microcephaly (head circumference significantly smaller than expected for the child’s age and sex). Some children also show impaired cognitive development and reduced activity of the testes or ovaries (hypothalamic hypogonadism).

WMS is caused by mutations in one of at least four different genes: RAB18, RAB3GAP1, RAB3GAP2, or TCB1D20. The syndrome is inherited in an autosomal recessive manner, meaning a child must inherit a defective gene from each parent, while the parents are typically healthy carriers.

In 1993, Warburg coined the term MICRO syndrome to describe a disorder characterized by microcephaly, microcornea, congenital cataracts, intellectual disability, optic nerve atrophy, and hypogonadism. WMS is part of a spectrum of disorders that includes Martsolf syndrome, which involves abnormalities on the short arm of a chromosome and mutations in the RAB3GAP2 gene associated with Martsolf syndrome.

Although scientists have been able to define the syndrome with its characteristic features, much about Warburg Micro syndrome (WMS) remains unknown. The small number of diagnosed cases, lack of large clinical studies, and potential influence of other genes that modify or mimic the disorder prevent clinicians from developing a complete picture of associated symptoms and determining a definitive prognosis. Therefore, it is important to note that affected individuals may not exhibit all of the symptoms listed below. Each child is unique, and prognosis is individualized.

Children with WMS have vision and eye problems. These include abnormally small eyes (microphthalmia) and abnormally small corneas (microcornea). The corneas are usually transparent, particularly the superficial layers. Some children are born with congenital cataracts, which typically affect both eyes. Degeneration of the optic nerve (optic nerve atrophy) may also occur. The optic nerve is the primary nerve in the visual pathway, transmitting impulses and visual perception to the brain’s visual centers. Vision impairment in affected individuals can result from optic nerve atrophy or damage to the brain’s visual cortex (cortical atrophy). Some children with WMS may also develop glaucoma.

Children with WMS may have atonic pupils. These pupils are abnormally large, irregularly shaped, and respond poorly to light—they constrict only weakly. Normally, the pupil constricts in bright light or when focusing on near objects, and dilates (mydriasis) in dim light or darkness, when focusing on distant objects, or in response to emotional stimuli.

Children with Warburg Micro syndrome (WMS) typically present with intellectual disability, often of severe degree. Some children are unable to sit, walk, or speak independently. Autism may develop in some cases, and seizures are occasionally observed.

Several brain development abnormalities are associated with WMS. These include underdevelopment of the corpus callosum, which connects the right and left hemispheres (corpus callosum hypoplasia), underdevelopment of the brain (cortical atrophy), progressive shrinkage of the cerebellum, which controls movement coordination (cerebellar atrophy), and polymicrogyria—a condition in which there are excessive small folds in the cerebral cortex. Some children may experience delayed myelination. The myelin sheath covers and protects nerve fibers, acting as an insulator and increasing the speed of nerve signal transmission. Brain findings can vary and are individualized for each child with WMS.

Children with WMS also have growth impairment and may exhibit low muscle tone (hypotonia). Later, muscle tone may increase, potentially progressing to spasticity, particularly in the lower limbs. Spasticity can cause stiffness and joint contractures, partially or completely limiting movement. Progressive muscle weakness may develop, which can advance to paralysis of both upper and lower limbs (quadriplegia).

Some children have underdeveloped or poorly functioning testes or ovaries (hypothalamic hypogonadism). Affected boys may have a small penis, underdeveloped scrotum, and undescended testes. Affected girls may have underdeveloped clitoris and labia, with an unusually small vaginal opening (introitus). Hypogonadism in girls may be mild or go unnoticed.

Facial abnormalities are common, including narrow mouth, broad nasal bridge, and deep-set eyes. Other reported features include abnormal curvature of the spine (kyphoscoliosis) and excessive hair growth (hypertrichosis).

Diagnostics:
Warburg Micro syndrome (WMS) is caused by mutations in at least four different genes. The four genes currently known to be associated with the disorder are RAB18, RAB3GAP1, RAB3GAP2, and TBC1D20. Not all patients have identifiable mutations in these genes, suggesting that additional, currently unknown genes may also contribute to WMS.

These genes encode proteins that play critical roles in many bodily functions. When a gene is mutated, its protein product may be defective, ineffective, or absent. Depending on the specific protein’s function, this can affect multiple organ systems, including the brain and eyes.

Genetic changes causing WMS are inherited in an autosomal recessive manner. Most genetic disorders of this type occur when an individual inherits two copies of a gene—one from the father and one from the mother. Recessive genetic disorders arise when a person inherits two abnormal copies of a gene, one from each parent. If an individual inherits one normal gene and one mutated gene, they are a carrier but usually show no symptoms.

For parents who are healthy carriers, the risk of having a child with WMS is 25%, a 50% chance the child will be a healthy carrier, and a 25% chance the child will inherit two normal genes. The risk is the same for male and female children. All affected individuals carry 7–8 abnormal genes. Parents who are closely related have a higher likelihood of carrying the same abnormal gene, increasing the risk of their children inheriting this recessive genetic disorder.

Warburg Micro syndrome is an extremely rare disorder. As with many rare conditions, the exact incidence or prevalence is unknown. The syndrome is often misdiagnosed or undiagnosed, which complicates determination of its true frequency in the population. Fewer than 100 individuals with this disorder have been reported in the medical literature.

Treatment:
Treatment is symptomatic, focusing on managing the symptoms and impairments associated with the disorder.

Warburg Micro syndrome

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